Mammalian presenilins consist of two homologous proteins: PS1 and PS2. They are indispensable for the proteolytic processing of a variety of substrates including Notch and the amyloid precursor protein (APP), molecules that play critical roles in cell fate determination and Alzheimer's disease (AD) pathogenesis, respectively. In addition, PS1 associates with beta-catenin---a multi-functional protein involved in cell adhesion, Wnt signaling and tumorigenesis. The original application was aimed at investigating the role of PS 1-beta-catenin pathway in skin tumorigenesis and dissecting the PSI-mediated activities in vivo. We have achieved all of our objectives within the grant-funding period. We reported that PS 1 facilitates beta-catenin turnover. As such, loss of PS 1 is associated with enhanced beta-catenin signaling, activation of its downstream target cyclin D1, accelerated cell proliferation and skin tumorigenesis in mice. Using our novel human PS1 "rescue" system in which expression of wild-type PSI could rescue the mouse PS1 null lethal phenotype, we established that a) PS 1 in Notch processing and beta-catenin interaction can be genetically and functionally uncoupled; and b) Aspartate 257 of PS 1 is critical for Notch and APP proteolysis, thus providing strong support that these two pathways are mediated through the same mechanisms. Two important findings emerged during the course of the study: a) We discovered a widespread role of presenilins in regulating cell proliferation and tumorigenesis: Presenilin deficiency leads to age-dependent myeloproliferative defect indicative of human chronic myelogenous leukemia (CML). Investigating the nature of the defect and determining the molecular mechanisms of presenilins in hematopoiesis is one of the research topics of the current application; b) We established a potent and specific regulation of cyclin D1 by presenilins in both mitotic cells and developing neurons. This observation, combined with the fact that activation of cyclin D1 is an early marker in degenerating neurons of AD patients, leads to an appealing hypothesis that compromised presenilin function, by genetic or environmental insults could result in deregulation of cyclin D1 and unscheduled cell cycle re-entry, with the outcome of neoplasia in peripheral tissues and neurodegeneration in the central nervous system. This competitive renewal is aimed at experimental approaches to test this hypothesis using our powerful mouse genetic systems. The studies combined will significantly advance our understanding of the molecular mechanisms underlying presenilin activities in tumorigenesis, neurodegeneration and AD pathogenesis.